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2.  Broadly neutralizing antibodies that inhibit HIV-1 cell to cell transmission 
The Journal of Experimental Medicine  2013;210(13):2813-2821.
A subset of broadly neutralizing anti-HIV antibodies inhibits cell to cell transmission of the virus.
The neutralizing activity of anti–HIV-1 antibodies is typically measured in assays where cell-free virions enter reporter cell lines. However, HIV-1 cell to cell transmission is a major mechanism of viral spread, and the effect of the recently described broadly neutralizing antibodies (bNAbs) on this mode of transmission remains unknown. Here we identify a subset of bNAbs that inhibit both cell-free and cell-mediated infection in primary CD4+ lymphocytes. These antibodies target either the CD4-binding site (NIH45-46 and 3BNC60) or the glycan/V3 loop (10-1074 and PGT121) on HIV-1 gp120 and act at low concentrations by inhibiting multiple steps of viral cell to cell transmission. These antibodies accumulate at virological synapses and impair the clustering and fusion of infected and target cells and the transfer of viral material to uninfected T cells. In addition, they block viral cell to cell transmission to plasmacytoid DCs and thereby interfere with type-I IFN production. Thus, only a subset of bNAbs can efficiently prevent HIV-1 cell to cell transmission, and this property should be considered an important characteristic defining antibody potency for therapeutic or prophylactic antiviral strategies.
PMCID: PMC3865481  PMID: 24277152
3.  Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease 
Escott-Price, Valentina | Bellenguez, Céline | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Jones, Lesley | Holmans, Peter | Gerrish, Amy | Vedernikov, Alexey | Richards, Alexander | DeStefano, Anita L. | Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A. | Naj, Adam C. | Sims, Rebecca | Jun, Gyungah | Bis, Joshua C. | Beecham, Gary W. | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A. | Denning, Nicola | Smith, Albert V. | Chouraki, Vincent | Thomas, Charlene | Ikram, M. Arfan | Zelenika, Diana | Vardarajan, Badri N. | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L. | Vronskaya, Maria | Johnson, Andrew D. | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L. | Buxbaum, Joseph D. | Campion, Dominique | Crane, Paul K. | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L. | De Jager, Philip L. | Deramecourt, Vincent | Johnston, Janet A. | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Hernández, Isabel | Rubinsztein, David C. | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M. | Fiévet, Nathalie | Huentelman, Matthew J. | Gill, Michael | Brown, Kristelle | Kamboh, M. Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B. | Myers, Amanda J. | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W. | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick C. | Hardy, John | Naranjo, Maria Candida Deniz | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Scarpini, Elio | Bonuccelli, Ubaldo | Mancuso, Michelangelo | Siciliano, Gabriele | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Frank-García, Ana | Panza, Francesco | Solfrizzi, Vincenzo | Caffarra, Paolo | Nacmias, Benedetta | Perry, William | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M. | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G. | Coto, Eliecer | Hamilton-Nelson, Kara L. | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J. | Faber, Kelley M. | Jonsson, Palmi V. | Combarros, Onofre | O'Donovan, Michael C. | Cantwell, Laura B. | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H. | Bennett, David A. | Harris, Tamara B. | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F. A. G. | Passmore, Peter | Montine, Thomas J. | Bettens, Karolien | Rotter, Jerome I. | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M. | Kukull, Walter A. | Hannequin, Didier | Powell, John F. | Nalls, Michael A. | Ritchie, Karen | Lunetta, Kathryn L. | Kauwe, John S. K. | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R. | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M. | Graff, Caroline | Psaty, Bruce M. | Haines, Jonathan L. | Lathrop, Mark | Pericak-Vance, Margaret A. | Launer, Lenore J. | Van Broeckhoven, Christine | Farrer, Lindsay A. | van Duijn, Cornelia M. | Ramirez, Alfredo | Seshadri, Sudha | Schellenberg, Gerard D. | Amouyel, Philippe | Williams, Julie
PLoS ONE  2014;9(6):e94661.
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal Findings
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
PMCID: PMC4055488  PMID: 24922517
4.  Opioid antagonists for smoking cessation 
The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking.
To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone.
Search methods
We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using ’Narcotic antagonists’ and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies.
Selection criteria
We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence.
Data collection and analysis
We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel-Haenszel fixed-effect model.
Main results
Eight trials of naltrexone met inclusion criteria for meta-analysis of long-term cessation. One trial used a factorial design so five trials compared naltrexone versus placebo and four trials compared naltrexone plus nicotine replacement therapy (NRT) versus placebo plus NRT. Results from 250 participants in one long-term trial remain unpublished. No significant difference was detected between naltrexone and placebo (risk ratio (RR) 1.00; 95% confidence interval (CI) 0.66 to 1.51, 445 participants), or between naltrexone and placebo as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30, 768 participants). The estimate was similar when all eight trials were pooled (RR 0.97; 95% CI 0.76 to 1.24, 1213 participants). In a secondary analysis of abstinence at end of treatment, there was also no evidence of any early treatment effect, (RR 1.03; 95% CI 0.88 to 1.22, 1213 participants). No trials of naloxone or buprenorphine reported abstinence outcomes.
Authors’ conclusions
Based on data from eight trials and over 1200 individuals, there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, with a point estimate strongly suggesting no effect and confidence intervals that make a clinically important effect of treatment unlikely. Although further trials might narrow the confidence intervals they are unlikely to be a good use of resources.
PMCID: PMC4038652  PMID: 23744347
Buprenorphine [therapeutic use]; Naloxone [therapeutic use]; Naltrexone [therapeutic use]; Narcotic Antagonists [*therapeutic use]; Randomized Controlled Trials as Topic; Smoking [*drug therapy]; Smoking Cessation [*methods]; Tobacco Use Cessation Products; Humans
5.  All in Its Proper Time: Monitoring the Emergence of a Memory Bias for Novel, Arousing-Negative Words in Individuals with High and Low Trait Anxiety 
PLoS ONE  2014;9(6):e98339.
The well-established memory bias for arousing-negative stimuli seems to be enhanced in high trait-anxious persons and persons suffering from anxiety disorders. We monitored the emergence and development of such a bias during and after learning, in high and low trait anxious participants. A word-learning paradigm was applied, consisting of spoken pseudowords paired either with arousing-negative or neutral pictures. Learning performance during training evidenced a short-lived advantage for arousing-negative associated words, which was not present at the end of training. Cued recall and valence ratings revealed a memory bias for pseudowords that had been paired with arousing-negative pictures, immediately after learning and two weeks later. This held even for items that were not explicitly remembered. High anxious individuals evidenced a stronger memory bias in the cued-recall test, and their ratings were also more negative overall compared to low anxious persons. Both effects were evident, even when explicit recall was controlled for. Regarding the memory bias in anxiety prone persons, explicit memory seems to play a more crucial role than implicit memory. The study stresses the need for several time points of bias measurement during the course of learning and retrieval, as well as the employment of different measures for learning success.
PMCID: PMC4041778  PMID: 24887093
6.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease 
Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A | Harold, Denise | Naj, Adam C | Sims, Rebecca | Bellenguez, Céline | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao-Feng | Gerrish, Amy | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Choi, Seung-Hoan | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Ramirez, Alfredo | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Morón, Francisco J | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Green, Robert | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | St George-Hyslop, Peter | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petroula | Collinge, John | Sorbi, Sandro | Sanchez-Garcia, Florentino | Fox, Nick C | Hardy, John | Deniz Naranjo, Maria Candida | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Matthews, Fiona | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O’Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F A G | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John S K | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Schmidt, Reinhold | Rujescu, Dan | Wang, Li-san | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Jones, Lesley | Haines, Jonathan L | Holmans, Peter A | Lathrop, Mark | Pericak-Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broeckhoven, Christine | Moskvina, Valentina | Seshadri, Sudha | Williams, Julie | Schellenberg, Gerard D | Amouyel, Philippe
Nature genetics  2013;45(12):1452-1458.
Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.
PMCID: PMC3896259  PMID: 24162737
7.  Nutrition education and leadership for improved clinical outcomes: training and supporting junior doctors to run ‘Nutrition Awareness Weeks’ in three NHS hospitals across England 
BMC Medical Education  2014;14:109.
One in four adults are estimated to be at medium to high risk of malnutrition when screened using the ‘Malnutrition Universal Screening Tool’ upon admission to hospital in the United Kingdom. The Need for Nutrition Education/Education Programme (NNEdPro) Group was developed to address this issue and the Nutrition Education and Leadership for Improved Clinical Outcomes (NELICO) is a project within this group.
The objective of NELICO was to assess whether an intensive training intervention combining clinical and public health nutrition, organisational management and leadership strategies, could equip junior doctors to contribute to improvement in nutrition awareness among healthcare professionals in the National Health Service in England.
Three junior doctors were self-selected from the NNEdPro Group original training. Each junior doctor recruited three additional team members to attend an intensive training weekend incorporating nutrition, change management and leadership. This equipped them to run nutrition awareness weeks in their respective hospitals. Knowledge, attitudes and practices were evaluated at baseline as well as one and four months post-training as a quality assurance measure. The number and type of educational events held, pre-awareness week Online Hospital Survey results, attendance and qualitative feedback from training sessions, effectiveness of dissemination methods such as awareness stalls, Hospital Nutrition Attitude Survey results and overall feedback were also used to determine impact.
When the weighted average score for knowledge, attitudes and practices at baseline was compared with four months post-intervention scores, there was a significant increase in the overall score (p = 0.03). All three hospital teams conducted an effective nutrition awareness week, as determined by qualitative data collected from interviews and feedback from educational sessions.
The NELICO project and its resulting nutrition awareness weeks were considered innovative in terms of concept and content. It was considered useful, both for the junior doctors who showed improvement in their nutrition knowledge and reported enthusiasm and for the hospital setting, increasing awareness of clinical and public health nutrition among healthcare professionals. The NELICO project is one innovative method to promote nutrition awareness in tomorrow’s doctors and shows they have the enthusiasm and drive to be nutrition champions.
PMCID: PMC4059452  PMID: 24885676
Nutrition; Education; Medical; Doctors
8.  Draft Genome Sequence of Pantoea ananatis Strain LMG 2665T, a Bacterial Pathogen of Pineapple Fruitlets 
Genome Announcements  2014;2(3):e00489-14.
We report the draft genome sequence of Pantoea ananatis LMG 2665T, the bacterial causal agent of pineapple fruitlet rot.
PMCID: PMC4031347  PMID: 24855311
9.  GlycoPep Detector: A tool for assigning mass spectrometry data of N-linked glycopeptides based on their ETD spectra 
Analytical chemistry  2013;85(10):10.1021/ac400287n.
Electron transfer dissociation (ETD) is commonly used in fragmenting N-linked glycopeptides in their mass spectral analyses to complement collision induced dissociation (CID) experiments. The glycan remains intact through ETD, while the peptide backbone is cleaved, providing the sequence of amino acids for a glycopeptide. Nonetheless, data analysis is a major bottleneck to high throughput glycopeptide identification based on ETD data, due to the complexity and diversity of ETD mass spectra compared to CID counterparts. GlycoPep Detector (GPD) is a web-based tool to address this challenge. It filters out noise peaks that interfere with glycopeptide sequencing, correlates input glycopeptide compositions with the ETD spectra, and assigns a score for each candidate. By considering multiple ion series (c-, z- and y-ions) and scoring them separately, the software gives more weighting to the ion series that matches peaks of high intensity in the spectra. This feature enables the correct glycopeptide to receive a high score while keeping scores of incorrect compositions low. GPD has been utilized to interpret data collected on six model glycoproteins (RNase B, avidin, fetuin, asialofetuin, transferrin and AGP) as well as a clade C HIV envelope glycoprotein, C.97ZA012 gp140ΔCFI. In every assignment made by GPD, the correct glycopeptide composition earns a score that is about two-fold higher than other incorrect glycopeptide candidates (decoys). The software can be accessed at
PMCID: PMC3837445  PMID: 23510108
10.  Developmental Differences for Word Processing in the Ventral Stream 
Brain and language  2012;125(2):134-145.
The Visual Word Form System (VWFS), located in the occipito-temporal cortex, is involved in orthographic processing of visually presented words (Cohen et al., 2002). Recent fMRI studies in children and adults have demonstrated a gradient of increasing word-selectivity along the posterior-to-anterior axis of this system (Vinckier et al., 2007), yet whether this pattern is modified by the increased reading experience afforded by age is still in question. In this study, we employed fMRI and an implicit word-processing task, and then used a region of interest analysis approach along the occipito-temporal cortex to test the prediction that the selectivity for words along the extent of the VWFS differs between older experienced and younger novice readers. Our results showed differences between children and adults during word processing in the anterior left occipito-temporal cortex, providing evidence of developmental refinement for word recognition along the VWFS.
PMCID: PMC3426643  PMID: 22564748
Neural development; ventral stream; occipito-temporal cortex; reading acquisition; fMRI; regions of interest
11.  Repeat expansions in the C9ORF72 gene contribute to Alzheimer disease in Caucasians 
Neurobiology of aging  2012;34(5):1519.e5-1519.e12.
Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer disease (AD), we hypothesized that C9ORF72 expansions may contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a rate of 0.76% in AD cases versus zero in controls (p=3.3E-03, 1,182 cases, 1,039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0–23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological reevaluation of identified C9ORF72 expansion carriers revealed nine clinical and/or autopsy confirmed AD and two FTD finial diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.
PMCID: PMC3586789  PMID: 23107433
C9ORF72; repeat expansion; Alzheimer Disease; genetic association; repeat-primed PCR; spectrum of neurodegenerative phenotypes
12.  Have we met before? Neural correlates of emotional learning in women with social phobia 
Altered memory processes are thought to be a key mechanism in the etiology of anxiety disorders, but little is known about the neural correlates of fear learning and memory biases in patients with social phobia. The present study therefore examined whether patients with social phobia exhibit different patterns of neural activation when confronted with recently acquired emotional stimuli.
Patients with social phobia and a group of healthy controls learned to associate pseudonames with pictures of persons displaying either a fearful or a neutral expression. The next day, participants read the pseudonames in the magnetic resonance imaging scanner. Afterwards, 2 memory tests were carried out.
We enrolled 21 patients and 21 controls in our study. There were no group differences for learning performance, and results of the memory tests were mixed. On a neural level, patients showed weaker amygdala activation than controls for the contrast of names previously associated with fearful versus neutral faces. Social phobia severity was negatively related to amygdala activation. Moreover, a detailed psychophysiological interaction analysis revealed an inverse correlation between disorder severity and frontolimbic connectivity for the emotional > neutral pseudonames contrast.
Our sample included only women.
Our results support the theory of a disturbed corticolimbic interplay, even for recently learned emotional stimuli. We discuss the findings with regard to the vigilance–avoidance theory and contrast them to results indicating an oversensitive limbic system in patients with social phobia.
PMCID: PMC3997608  PMID: 24758944
13.  SOSORT 2012 consensus paper: reducing x-ray exposure in pediatric patients with scoliosis 
Scoliosis  2014;9:4.
This 2012 Consensus paper reviews the literature on side effects of x-ray exposure in the pediatric population as it relates to scoliosis evaluation and treatment. Alternative methods of spinal assessment and imaging are reviewed, and strategies for reducing the number of radiographs are developed. Using the Delphi technique, SOSORT members developed consensus statements that describe how often radiographs should be taken in each of the pediatric and adolescent sub-populations.
PMCID: PMC4002921  PMID: 24782912
14.  Knowledge, Attitudes, and Practices of Nonpharmaceutical Interventions following School Dismissals during the 2009 Influenza A H1N1 Pandemic in Michigan, United States 
PLoS ONE  2014;9(4):e94290.
Many schools throughout the United States reported an increase in dismissals due to the 2009 influenza A H1N1 pandemic (pH1N1). During the fall months of 2009, more than 567 school dismissals were reported from the state of Michigan. In December 2009, the Michigan Department of Community Health, in collaboration with the United States Centers for Disease Control and Prevention, conducted a survey to describe the knowledge, attitudes, and practices (KAPs) of households with school-aged children and classroom teachers regarding the recommended use of nonpharmaceutical interventions (NPIs) to slow the spread of influenza.
A random sample of eight elementary schools (kindergarten through 5th grade) was selected from each of the eight public health preparedness regions in the state. Within each selected school, a single classroom was randomly identified from each grade (K-5), and household caregivers of the classroom students and their respective teachers were asked to participate in the survey.
In total, 26% (2,188/8,280) of household caregivers and 45% (163/360) of teachers from 48 schools (of the 64 sampled) responded to the survey. Of the 48 participating schools, 27% (13) experienced a school dismissal during the 2009 fall term. Eighty-seven percent (1,806/2,082) of caregivers and 80% (122/152) of teachers thought that the 2009 influenza A H1N1 pandemic was severe, and >90% of both groups indicated that they told their children/students to use NPIs, such as washing hands more often and covering coughs with tissues, to prevent infection with influenza.
Knowledge and instruction on the use of NPIs appeared to be high among household caregivers and teachers responding to the survey. Nevertheless, public health officials should continue to explain the public health rationale for NPIs to reduce pandemic influenza. Ensuring this information is communicated to household caregivers and teachers through trusted sources is essential.
PMCID: PMC3991575  PMID: 24747300
15.  The emergence and evolution of the novel epidemic norovirus GII.4 variant Sydney 2012 
Virology  2013;0:106-113.
Norovirus is the leading cause of acute gastroenteritis with most infections caused by GII.4 variants. To understand the evolutionary processes that contribute to the emergence of GII.4 variants, we examined the molecular epidemiology of norovirus-associated acute gastroenteritis in Australia and New Zealand from 893 outbreaks between 2009 and 2012. Throughout the study GII.4 New Orleans 2009 was predominant; however, during 2012 it was replaced by an emergent GII.4 variant, Sydney 2012. An evolutionary analysis of capsid gene sequences was performed to determine the origins and selective pressures driving the emergence of these recently circulating GII.4 variants. This revealed that both New Orleans 2009 and Sydney 2012 share a common ancestor with GII.4 Apeldoorn 2007. Furthermore, pre-epidemic ancestral variants of each virus were identified up to two years before their pandemic emergence. Adaptive changes at known blockade epitopes in the viral capsid were also identified that likely contributed to their emergence.
PMCID: PMC3984403  PMID: 24503072
Norovirus; Gastroenteritis; Emergence; Evolution; Sydney 2012
16.  The statistical analysis of partially confounded covariates important to neural spiking 
Journal of neuroscience methods  2012;205(2):295-304.
A method is presented capable of disambiguating the relative influence of statistical covariates upon neural spiking activity. The method, an extension of the generalized linear model (GLM) methodology introduced in Truccolo et al. (2005) to analyze neural spiking data, exploits projection operations motivated by a geometry present in the Fisher information of the GLM maximum likelihood parameter estimator. By exploiting these projections, neural activity can be divided into three categories. These three categories, neural activity due solely to a set of covariates of interest, neural activity due solely to a set of uninteresting, or nuisance, covariates, and neural activity that cannot be unequivocally assigned to either set of covariates, can be associated with physical variables such as time, position, head-direction and velocity. This association allows the analysis of neural activity that can, for example, be due solely to temporal influence, irrespective of other, identified, influences. The method is applied in simulation to a rat exploring a temporally modulated place field. A portion of the analysis reported in MacDonald et al. (2011), using the methodology described herein, is reproduced. This analysis demonstrates the temporal bridging of a delay period in a sequential memory task by firing activity of cells present in the rodent hippocampus that cannot be explained by rodent position, head direction or velocity.
PMCID: PMC3976545  PMID: 22281297
Neural activity disambiguation; Confound; Covariate disambiguation; Generalized linear model; Projection; Point process
17.  Association of Single-Nucleotide Polymorphisms of the Tau Gene With Late-Onset Parkinson Disease 
The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease.
To investigate whether the tau gene is involved in idiopathic PD.
Design, Setting, and Participants
Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene.
Main Outcome Measure
Family-based tests of association, calculated using asymptotic distributions.
Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P = .03; SNP 9i, P = .04; and SNP 11, P = .04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P = .11, and SNP 9iii, P = .87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P = .009) and a negative association with another haplotype (P = .007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3,9i, 9ii, and 11).
This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.
PMCID: PMC3973175  PMID: 11710889
18.  Knowledge of Obesity and Its Impact on Reproductive Health Outcomes Among Urban Women 
Journal of community health  2013;38(2):261-267.
This prospective survey study assessed the knowledge of reproductive outcomes that are affected by obesity among women in an urban community. A total of 207 women attending a community fair on the south side of Chicago participated in the study. A survey assessing knowledge of BMI and of the effects of obesity on general, cardiometabolic and reproductive health outcomes was administered. Subjects ranged in age from 18 to 70 years (mean ± SD, 48.6 ± 12.9 years) and ranged in BMI from 17.3 to 52.1 kg/m2 (mean ± SD, 31.2 ± 6.7 kg/m2). The following percentages of women were aware that obesity increases the risk of miscarriage (37.5%), irregular periods (35.8%), infertility (33.9%), cesarean section (30.8%), breast cancer (28.0%), birth defects (23.7%), stillbirth (14.1%), and endometrial cancer (18.1%). This study found that while women in an urban community are aware of the cardiometabolic risks associated with obesity, they demonstrate limited knowledge of the effects of obesity on reproductive outcomes. Public education is needed to increase knowledge and awareness of the reproductive consequences of obesity. Women of reproductive age may be uniquely responsive to obesity education and weight loss intervention.
PMCID: PMC3563852  PMID: 22961295
community health; knowledge; obesity; reproduction; women
19.  Distinct injury markers for the early detection and prognosis of incident acute kidney injury in critically ill adults with preserved kidney function 
Kidney international  2013;84(4):786-794.
The use of novel biomarkers to detect incident acute kidney injury (AKI) in the critically ill is hindered by heterogeneity of injury and the potentially confounding effects of prevalent AKI. Here we examined the ability of urine NGAL (NGAL), L-type Fatty Acid Binding Protein (L-FABP), and Cystatin C to predict AKI development, death, and dialysis in a nested case-control study of 380 critically ill adults with an eGFR over 60 ml/min/1.73 m2. One-hundred thirty AKI cases were identified following biomarker measurement and were compared to 250 controls without AKI. Areas under the receiver-operator characteristic curves (AUC-ROCs) for discriminating incident AKI from non-AKI were 0.58(95%CI: 0.52-0.64), 0.59(0.52-0.65), and 0.50(0.48-0.57) for urine NGAL, L-FABP, and Cystatin C, respectively. The combined AUC-ROC for NGAL and L-FABP was 0.59(56-0.69). Both urine NGAL and L-FABP independently predicted AKI during multivariate regression; however, risk reclassification indices were mixed. Neither urine biomarker was independently associated with death or acute dialysis [NGAL hazard ratio 1.35(95%CI: 0.93-1.96), L-FABP 1.15(0.82-1.61)] though both independently predicted the need for acute dialysis [NGAL 3.44(1.73-6.83), L-FABP 2.36(1.30-4.25)]. Thus, urine NGAL and L-FABP independently associated with the development of incident AKI and receipt of dialysis but exhibited poor discrimination for incident AKI using conventional definitions.
PMCID: PMC3788840  PMID: 23698227
20.  Exome Sequencing and Genome-Wide Linkage Analysis in 17 Families Illustrates the Complex Contribution of TTN Truncating Variants to Dilated Cardiomyopathy 
Circulation. Cardiovascular genetics  2013;6(2):10.1161/CIRCGENETICS.111.000062.
Familial dilated cardiomyopathy is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic dilated cardiomyopathy (DCM) cases.
Methods and Results
We used an unbiased genome-wide approach employing both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, MLOD 1.59. We identified six TTN truncating variants carried by affected with DCM in 7 of 17 DCM families (LOD 2.99); 2 of these 7 families also had novel missense variants segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable to five other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ~5,400 cases from the Exome Sequencing Project was ~23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity LOD score of 1.74.
These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.
PMCID: PMC3815606  PMID: 23418287
genetics; human; genome-wide analysis; dilated cardiomyopathy; exome
21.  A high-throughput chemical screen with FDA approved drugs reveals that the antihypertensive drug Spironolactone impairs cancer cell survival by inhibiting homology directed repair 
Nucleic Acids Research  2014;42(9):5689-5701.
DNA double-strand breaks (DSBs) are the most severe type of DNA damage. DSBs are repaired by non-homologous end-joining or homology directed repair (HDR). Identifying novel small molecules that affect HDR is of great importance both for research use and therapy. Molecules that elevate HDR may improve gene targeting whereas inhibiting molecules can be used for chemotherapy, since some of the cancers are more sensitive to repair impairment. Here, we performed a high-throughput chemical screen for FDA approved drugs, which affect HDR in cancer cells. We found that HDR frequencies are increased by retinoic acid and Idoxuridine and reduced by the antihypertensive drug Spironolactone. We further revealed that Spironolactone impairs Rad51 foci formation, sensitizes cancer cells to DNA damaging agents, to Poly (ADP-ribose) polymerase (PARP) inhibitors and cross-linking agents and inhibits tumor growth in xenografts, in mice. This study suggests Spironolactone as a new candidate for chemotherapy.
PMCID: PMC4027216  PMID: 24682826
22.  Systematic review and meta-analysis of opioid antagonists for smoking cessation 
BMJ Open  2014;4(3):e004393.
This meta-analysis sought to evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. Post-treatment abstinence was examined as a secondary outcome and effects on withdrawal symptoms, craving and reduced consumption were also explored.
The search strategy for this meta-analysis included clinical trials (published and unpublished data) in the Cochrane Tobacco Addiction Group Specialized Register and MEDLINE.
Adult smokers.
We included randomised trials comparing opioid antagonists to placebo or an alternative therapy for smoking cessation and reported data on abstinence for a minimum of 6 months.
Primary and secondary outcome measures
Outcomes included smoking abstinence at long-term follow-up (primary); abstinence at end of treatment (secondary); and effects on withdrawal, craving and smoking consumption (exploratory).
8 trials with a total of 1213 participants were included. Half the trials examined the benefit of adding naltrexone versus placebo to nicotine replacement therapy (NRT). There was no significant difference between naltrexone and placebo alone (relative risk (RR) 1.00; 95% CI 0.66 to 1.51) or as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30), with an overall pooled estimate of RR 0.97; 95% CI 0.76 to 1.24. Findings for naltrexone effects on withdrawal, craving and reduced smoking were equivocal.
The findings indicate no beneficial effect of naltrexone alone or as an adjunct to NRT on short-term or long-term smoking abstinence. While further trials may narrow the confidence limits, they are unlikely to appreciably alter the conclusion.
PMCID: PMC3963070  PMID: 24633528
opioid antagonists ; smoking cessation; tobacco; smoking abstinence; naltrexone
23.  Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease 
Neurology  2013;80(11):982-989.
Recently, vacuolar protein sorting 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) have been identified as 2 causal Parkinson disease (PD) genes. We used whole exome sequencing for rapid, parallel analysis of variations in these 2 genes.
We performed whole exome sequencing in 213 patients with PD and 272 control individuals. Those rare variants (RVs) with <5% frequency in the exome variant server database and our own control data were considered for analysis. We performed joint gene-based tests for association using RVASSOC and SKAT (Sequence Kernel Association Test) as well as single-variant test statistics.
We identified 3 novel VPS35 variations that changed the coded amino acid (nonsynonymous) in 3 cases. Two variations were in multiplex families and neither segregated with PD. In EIF4G1, we identified 11 (9 nonsynonymous and 2 small indels) RVs including the reported pathogenic mutation p.R1205H, which segregated in all affected members of a large family, but also in 1 unaffected 86-year-old family member. Two additional RVs were found in isolated patients only. Whereas initial association studies suggested an association (p = 0.04) with all RVs in EIF4G1, subsequent testing in a second dataset for the driving variant (p.F1461) suggested no association between RVs in the gene and PD.
We confirm that the specific EIF4G1 variation p.R1205H seems to be a strong PD risk factor, but is nonpenetrant in at least one 86-year-old. A few other select RVs in both genes could not be ruled out as causal. However, there was no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development in our dataset.
PMCID: PMC3653206  PMID: 23408866
24.  Noise Genetics: Inferring Protein Function by Correlating Phenotype with Protein Levels and Localization in Individual Human Cells 
PLoS Genetics  2014;10(3):e1004176.
To understand gene function, genetic analysis uses large perturbations such as gene deletion, knockdown or over-expression. Large perturbations have drawbacks: they move the cell far from its normal working point, and can thus be masked by off-target effects or compensation by other genes. Here, we offer a complementary approach, called noise genetics. We use natural cell-cell variations in protein level and localization, and correlate them to the natural variations of the phenotype of the same cells. Observing these variations is made possible by recent advances in dynamic proteomics that allow measuring proteins over time in individual living cells. Using motility of human cancer cells as a model system, and time-lapse microscopy on 566 fluorescently tagged proteins, we found 74 candidate motility genes whose level or localization strongly correlate with motility in individual cells. We recovered 30 known motility genes, and validated several novel ones by mild knockdown experiments. Noise genetics can complement standard genetics for a variety of phenotypes.
Author Summary
Inferring the function of proteins and the role they play in cellular processes is essential for our understanding of cell biology, genetics and biology in general. Standard genetic approaches use large perturbations to cells such as gene knockout, knockdown or over expression of genes. Such methods are powerful, but have the drawback of taking the cell far from its normal working point. Here, we provide a new and much milder approach, which uses the natural cell-cell variation in protein level and expression pattern as a source of mild perturbation. We monitor individual live cancer cells under the microscope and correlate their protein levels and localization with phenotype in the same cells. We use the motility of human cancer cells as a model system that is highly important for understanding metastasis in cancer. We find that our approach uncovers most of the known motility proteins, as well as new ones which we validate using knockdown experiments. Our novel approach is widely applicable to any phenotype that can be visualized in individual cells, and for any organism for which one can measure proteins in individual cells.
PMCID: PMC3945223  PMID: 24603725
25.  Characterization of Host-Cell Line Specific Glycosylation Profiles of Early Transmitted/Founder HIV-1 gp120 Envelope Proteins 
Journal of proteome research  2013;12(3):1223-1234.
Glycosylation plays an essential role in regulating protein function by modulating biological, structural, and therapeutic properties. However, due to its inherent heterogeneity and diversity, the comprehensive analysis of protein glycosylation remains a challenge. As part of our continuing effort in the analysis of glycosylation profiles of recombinant HIV-1 envelope-based immunogens, we evaluated and compared the host-cell specific glycosylation pattern of recombinant HIV-1 surface glycoprotein, gp120, derived from clade C transmitted/founder virus 1086.C expressed in Chinese hamster ovary (CHO) and human embryonic kidney containing T antigen (293T) cell lines. We used an integrated glycopeptide-based mass mapping workflow that includes a partial deglycosylation step described in our previous study1 with the inclusion of the fragmentation technique, electron transfer dissociation (ETD), to complement collision induced dissociation (CID). The inclusion of ETD facilitated the analysis by providing additional validation for glycopeptide identification and expanding the identified glycopeptides to include coverage of O-linked glycosylation. The site-specific glycosylation analysis shows that the transmitted/founder 1086.C gp120 expressed in CHO and 293T displayed distinct similarities and differences. For N-linked glycosylation, two sites (N386 and N392), in the V4 region were populated with high mannose glycans in the CHO cell-derived 1086.C gp120, while these sites had a mixture of high mannose and processed glycans in the 293T cell-derived 1086.C gp120. Compositional analysis of O-linked glycans revealed that 293T cell-derived 1086.C gp120 consisted of cores 1, 2, and 4 type O-linked glycans while CHO cell-derived 1086.C exclusively consisted of core 1 type O-linked glycans. Overall, glycosylation site occupancy of the CHO and 293T cell-derived 1086.C gp120 show high degree of similarity except for one site at N88 in the C1 region. This site was partially occupied in 293T-gp120 but fully occupied in CHO-gp120. Site-specific glycopeptide analysis of transmitted/founder 1086.C gp120 expressed in CHO cells revealed the presence of phosphorylated glycans while 293T cell produced 1086.C gp120 glycans were not phosphorylated. While the influence of phosphorylated glycans on immunogenicity is unclear, distinguishing host-cell specific variations in glycosylation profiles provides insights into the similarity (or difference) in recombinant vaccine products. While these differences had minimal effect on envelope antigenicity, they may be important in considering immunogenicity and functional capacities of recombinant envelope proteins produced in different expression systems.
PMCID: PMC3674872  PMID: 23339644

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